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Simple Summary: Pancreatic cancer, notorious for its aggressive nature and complex desmoplastic tumor microenvironment, poses substantial treatment challenges, particularly in terms of early detection, and often exhibits resistance to standard chemotherapy and immunotherapy. Trametinib is a new therapeutic drug, a selective inhibitor of MEK1 and MEK2, which has shown promise in addressing these challenges. It not only hampers cancer cell division, angiogenesis, and metastatic spread but also significantly modifies the tumor microenvironment. This modification includes altering the activities of fibroblasts and immune cells, which are crucial in the cancer's progression and response to treatments. Several pivotal studies have highlighted trametinib's efficacy in reducing the proliferation of pancreatic cancer cells and enhancing the effectiveness of combined treatment regimens, especially in cases that show resistance to conventional therapies. The drug's potential to improve patient outcomes is currently under investigation in various clinical trials. These trials, encompassing different stages and forms of pancreatic cancer, are instrumental in determining the optimal use of trametinib, both as a single agent and in combination with other drugs. The ongoing research is crucial in defining trametinib's role in the evolving therapeutic landscape for pancreatic cancer, aiming to provide new avenues for treatment and potentially improve survival rates in this challenging disease area. Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug's effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib's mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Savolitinib is a highly specific inhibitor of the MET tyrosine kinase. Both preclinical and clinical studies have shown its potential as a treatment for various cancers, including non-small cell lung cancer (NSCLC) as well as breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. It can be used as a standalone treatment for NSCLC patients with MET mutations and in combination with EGFR inhibitors for those who have developed resistance. Moreover, it is being investigated as a neoadjuvant therapy. Furthermore, savolitinib has demonstrated efficacy in gastric cancer and may be effective in combination therapy. Additionally, it has shown effectiveness in treating renal cancer and other gastrointestinal cancers. Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the antiproliferative activity of Krukovine (KV) in oxaliplatin-resistant pancreatic cancer cells and explored the mechanism of action. KV suppresses tumor progression via the downregulation of the Erk-RPS6K-TMEM139 signaling pathway in oxaliplatin-resistant pancreatic cancer cells. Transmembrane protein 139 (TMEM139) has been identified as a novel oncogene and its overexpression has been associated with various types of cancer, including pancreatic cancer. In this study, KV significantly downregulated TMEM139 expression in oxaliplatin-resistant pancreatic cancer cells. The downregulation of TMEM139 by KV may contribute to its antiproliferative activity and could be a potential target for future therapeutic interventions. KV could be a potential therapeutic agent for the treatment of pancreatic cancer, particularly for patients with Kras mutations and oxaliplatin-resistant tumors. Krukovine (KV) is an alkaloid isolated from the bark of Abuta grandifolia (Mart.) Sandw. (Menispermaceae) with anticancer potential in some cancers with KRAS mutations. In this study, we explored the anticancer efficacy and mechanism of KV in oxaliplatin-resistant pancreatic cancer cells and patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutation. After treatment with KV, mRNA and protein levels were determined by RNA-seq and Western blotting, respectively. Cell proliferation, migration, and invasion were measured by MTT, scratch wound healing assay, and transwell analysis, respectively. Patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutations were treated with KV, oxaliplatin (OXA), and a combination of KV and OXA. KV suppresses tumor progression via the downregulation of the Erk-RPS6K-TMEM139 and PI3K-Akt-mTOR pathways in oxaliplatin-resistant AsPC-1 cells. Furthermore, KV showed an antiproliferative effect in PDPCOs, and the combination of OXA and KV inhibited PDPCO growth more effectively than either drug alone. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the efficacy and safety of gemcitabine plus nab-paclitaxel (GnP) as second-line chemotherapy following first-line FOLFIRINOX treatment failure in advanced pancreatic cancer. Methods: This was a multicenter, single-arm, open-label, phase 2 trial done at three tertiary centers in South Korea from May 2018 to December 2019. Eligible patients were aged 20 years or older, had histologically confirmed advanced pancreatic ductal adenocarcinoma, and disease progression after receiving first-line FOLFIRINOX. Patients received a second-line GnP regimen as intravenous nab-paclitaxel at a dose of 125 mg/m2 and gemcitabine at a dose of 1000 mg/m2, on days 1, 8, and 15 every 4 weeks until disease progression or unacceptable toxicity. The primary outcome was survival rate at 6 months and the secondary outcomes were median progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events. This study is registered with Clinicaltrials.gov. (NCT03401827) Results: Forty patients were enrolled in the study. The survival rate at 6 months was 72.5% [95% confidence interval (CI), 59.9–87.7], achieving superiority over prespecified assumed 6-month OS rate of 20% for best supportive care only (p < 0.001). The median PFS and OS were 5.8 months (95% CI, 4.3–8.7) and 9.9 months (95% CI, 7.5–12.4), respectively. DCR was 87.5% with six partial responses and 29 stable diseases. Grade 3 or higher treatment-related adverse events occurred in 25 (62.5%) patients with the most common being thrombocytopenia, anemia, neutropenia, peripheral neuropathy, and peripheral edema. Conclusion: GnP demonstrated favorable efficacy with acceptable toxicity in patients with advanced pancreatic ductal adenocarcinoma after FOLFIRINOX failure. [ABSTRACT FROM AUTHOR]

Background: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GnP) have been recommended as the first-line chemotherapy for metastatic pancreatic cancer (mPC). However, the evidence is lacking comparing not only two regimens, but also sequential treatment (FFX-GnP vs. GnP-FFX).Methods: Data of 528 patients (FFX, n = 371; GnP, n = 157) with mPC were collected retrospectively. Propensity score matching was conducted to alleviate imbalance of the two groups. Overall survival (OS), progression free survival (PFS), and toxicity of patients were analyzed.Results: In the whole population, OS (12.5 months vs. 10.3 months, P = 0.05) and PFS (7.1 months vs. 5.8 months, P = 0.02) were longer in the FFX group before matching and after matching (OS: 11.8 months vs. 10.3 months, P = 0.02; PFS: 7.2 months vs. 5.8 months, P <  0.01). For sequential treatment, OS and PFS showed no significant difference. Interruptions of chemotherapy due to toxicities were more frequent (6.8 vs. 29.3%, P <  0.001) in the GnP group, and cessation of chemotherapy showed a significant association with mortality (z = - 1.94, P = 0.03).Conclusions: FFX achieved a longer overall survival than GnP in mPC, but not in the comparison for sequential treatment. More frequent adverse events followed by treatment interruptions during GnP might lead to a poor survival outcome. Therefore, FFX would be a better first-line treatment option than GnP for mPC. [ABSTRACT FROM AUTHOR]

Background: Although several studies have suggested that aspirin and statins may help prevent pancreatic ductal adenocarcinoma (PDAC), this concept has been controversial. This study aimed to evaluate the association between use of statin or aspirin and PDAC in a nationwide large cohort. Methods: In this nested case‐control study, we used data from a 12‐year nationwide longitudinal cohort in Korea. Cases with PDAC and controls who were matched to cases by age, sex, income, and index year at a 1:5 ratio were established. We used multivariate logistic regression analyses to identify the independent risk factors of PDAC. Results: We identified a total of 827 patients with PDAC between 2007 and 2013, and included 4135 matched controls. Diabetes mellitus, chronic and acute pancreatitis, pancreatic cystic lesions, and cholelithiasis were independent risk factors for PDAC. Statin use (odds ratio [OR], 0.92; 95% confidence interval [CI] 0.76‐1.11; P = .344; adjusted OR [aOR], 0.70; 95% CI 0.56‐0.87; P = .001) was associated with a reduced risk of PDAC after correction of the confounding factors, but aspirin use (OR, 0.98; 95% CI 0.84‐1.15; P = .838; aOR 0.84; 95% CI 0.70‐1.01, P = .068) was not associated with PDAC. Among the patients with risk factors, both statin use (OR, 0.50; 95% CI 0.38‐0.66; P < .001; aOR, 0.62; 95% CI 0.45‐0.84; P = .002) and aspirin use (OR, 0.48; 95% CI 0.31‐0.67; P < .001; aOR 0.67; 95% CI 0.50‐0.89, P = .006) were associated with a reduced risk of PDAC. Conclusion: This study suggests that statin use was associated with a reduced risk of PDAC incidence but aspirin use was not. Both statin use and aspirin use were associated a reduced risk of PDAC incidence for patients with risk factors. [ABSTRACT FROM AUTHOR]

Background and Aim The role of carbohydrate antigen 19-9 (CA 19-9) for predicting treatment outcome in pancreatic ductal adenocarcinoma (PDAC) remains to be elucidated. This study was aimed to determine the correlation between early decrement in CA 19-9 concentration and prognosis of advanced PDAC after chemotherapy. Methods All patients confirmed with locally advanced or metastatic PDAC who received initial systemic chemotherapy for at least two cycles in our institution between January 2012 and December 2013 were included. Serum CA 19-9 concentrations at baseline and 8 weeks after the initiation of chemotherapy were obtained. Correlation between CA 19-9 decrement and survival outcomes (time to progression [TTP] and overall survival [OS]) were evaluated. Results A total of 183 patients with initially elevated CA 19-9 were included. OS and TTP was significantly longer for patients whose serum CA 19-9 concentration decreased more than 10% from baseline ( n = 103), than that for patients whose serum CA 19-9 was not decreased ( n = 80) (423 vs 155 days, P < 0.001 for OS and 222 vs 75 days, P < 0.001 for TTP). In multivariate analysis, CA 19-9 decrement more than 10% from baseline was still a significant factor for longer OS (hazard ratio for progression 0.275 [0.184-0.412], P < 0.001) and TTP (0.322 [0.219-0.473], P < 0.001) in both stage III and IV. Conclusions The early decrement of CA 19-9 after the initiation of chemotherapy was an independent factor related with better survival outcomes in unresectable PDAC. [ABSTRACT FROM AUTHOR]

Background and Aim: Self-expandable metal stents (SEMSs) have been a good treatment option for malignant intestinal obstruction. However, stent placement with a gastroscope can be technically difficult for the distal duodenum obstruction. A side-viewing duodenoscope may be helpful for these patients. We report our experiences in the insertion of SEMSs to distal duodenum with a side-viewing endoscope. Methods: We retrospectively analyzed our database of SEMS placement for malignant distal duodenum obstruction between April 2006 and April 2013. All patients underwent SEMS placement using the side-viewing endoscope (duodenoscope). Main outcomes are technical success, clinical success, complication rates, stent patency, and overall survival. In addition, database from other tertiary center was analyzed, where SEMS insertion was performed with forward-viewing endoscopes (gastroscope or colonoscope). Success and complication rates were compared with ours. Results: A total of 31 patients were reviewed. Pancreatic cancer was the most common cause (87.1 %). Technical and clinical success was achieved in all cases. Procedure-related complication occurred in one patient, who experienced micro-perforation of the duodenum. The patient improved with conservative treatment. Median duration of stent patency was 125 days (95 % CI 75-175), and median overall survival was 134 days (95 % CI 77-191). Biliary obstruction was present in 12.9 % of patients, who underwent biliary stent placement at the same time without changing endoscopes. In forward-viewing endoscopes group, 15 cases were included. Technical and clinical success was achieved in all cases, and no procedure-related complication occurred. Conclusions: The insertion of SEMSs to distal duodenum with a duodenoscope could be performed effectively and safely in patients with malignant obstruction. [ABSTRACT FROM AUTHOR]

Background/Aims: There is no standard consensus on a strategy in the second-line setting for gemcitabine-refractory advanced pancreatic cancer. This study evaluated the activity and tolerability of oxaliplatin, irinotecan, 5-fluorouracil and leucovorin (FOLFIRINOX) as a second-line therapy in advanced pancreatic adenocarcinoma pretreated with a gemcitabine-based regimen. Methods: A retrospective survey was carried out on 18 patients with advanced pancreatic cancer who had been on gemcitabine-based chemotherapy and were then treated with FOLFIRINOX as a second-line therapy. Results: One patient (5.6%) had a confirmed complete response, 4 (22.2%) had confirmed partial responses and 5 (27.8%) had stable disease, resulting in a rate of disease control of 55.6% (95% CI, 33.3-77.8%). The median progression-free survival and median survival were 2.8 months and 8.4 months, respectively. Seven patients (38.9%) experienced grade 3-4 neutropenia. Grade 3 or 4 nonhematologic adverse events included nausea (38.9%) and vomiting (16.7%). Conclusions: These results suggest the modest clinical activity regarding efficacy and the acceptable toxicity profile with the FOLFIRINOX regimen as a second-line treatment. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Life expectancy of pancreatic ductal adenocarcinoma (PDAC) patients is usually short and selection of the most appropriate treatment is crucial. The aim of this study was to investigate the usefulness of serum CA 19-9 as a surrogate marker under no impress excluding other factors affecting CA 19-9 level other than tumor itself. Methods: We recruited 1,446 patients with PDACs and patients with Lewis antigen both negative or obstructive jaundice were excluded to eliminate the false effects on CA 19-9 level. The clinicopathologic factors were reviewed including initial and post-treatment CA 19-9, and statistical analysis was done to evaluate the association of clinicopathologic factors with overall survival (OS). Results: The total of 944 patients was enrolled, and205 patients (22%) underwent operation with curative intention and 541 patients (57%) received chemotherapy and/or radiotherapy. The median CA 19-9 levels of initial and post-treatment were 670 IU/ml and 147 IU/ml respectively. The prognostic factors affecting OS were performance status, AJCC stage and post-treatment CA 19-9 level in multivariate analysis. Subgroup analysis was done for the patients who underwent R0 and R1 resection, and patients with normalized post-operative CA 19-9 (≤37 IU/mL) had significantly longer OS and DFS regardless of initial CA 19-9 level; 32 vs. 18 months, P<0.001, 16 vs. 9 months, P = 0.004 respectively. Conclusions: Post-treatment CA 19-9 and normalized post-operative CA 19-9 (R0 and R1 resected tumors) were independent factors associated with OS and DFS, however, initial CA 19-9 level was not statistically significant in multivariate analysis. [ABSTRACT FROM AUTHOR]

Background and aim Biliary self-expandable metallic stents ( SEMS) play an important role in the quality of life and palliative treatment in unresectable pancreatic cancer patients. We aimed to determine the factors affecting the patency of biliary SEMS and the survival in unresectable pancreatic cancer with obstructive jaundice. Methods Considering the competing risk and survival, we retrospectively evaluated the patency in 107 unresectable pancreatic cancer patients with obstructive jaundice who were successfully treated with biliary SEMS from January 2000 to April 2010. Results There were 107 incidents of biliary drainage that were clinically successful and the overall survival period was a median of 133 days. Stent occlusion before death was observed in 36 (33.6%) of 107 patients. Cumulative stent obstruction rates were4.7%, 16.8%, and 24.4% at 1, 3, and 6 months, respectively. Lower cancer stage (<5 month's hazard ratio [ HR] = 2.327, >5 month's HR = 0.108) was only associated with the longer patency of the stents in a multivariable analysis using a Fine and Gray model that considered competing risk. In multivariable analysis, lower cancer stage, uncovered stent and normalized serum bilirubin level were associated with a longer survival period ( HR = 2.335, 1.906 and 1.795 respectively, P < 0.05). Conclusion The patency of biliary SEMS in unresectable pancreatic cancers might be affected by the stage. Lower cancer stage and normalized bilirubin are associated with longer survival. [ABSTRACT FROM AUTHOR]

Background & Aims: Little information is available about the clinico-pathologic characteristics of pancreatic branch duct intraductal papillary mucinous neoplasm (Br-intraductal papillary mucinous neoplasm [IPMN]) because of difficulties in diagnosis based on radiologic and tissue information. We investigated the natural history of Br-IPMN using imaging and surgical pathology data from patients. Methods: Data were collected from patients admitted to a single tertiary referral institution from January 2000 to March 2009 (median follow up of 27.9 months); 201 patients were diagnosed with Br-IPMN with an initial cyst less than 30 mm without main pancreatic duct dilatation or mural nodules. The patients were followed for more than 3 months and examined by computed tomography (CT) at least twice. Results: The mean size of the patients'' initial cysts was 14.7 mm; the mean cyst growth rate was 1.1 mm/year. Thirty-five patients received surgery during follow up and 8 were confirmed to have malignant cysts. The malignant cysts were greater in final size than nonmalignant cysts (24.3 mm vs 16.9 mm; P = .003); they also grew by a greater percentage (69.8% vs 19.4%; P = .046) and at a greater rate (4.1 mm vs 1.0 mm/year; P = .001). The actuarial 5-year risk of malignancy was 41.6% in the group that received surgery and 10.9% for all patients. Cysts that grew more than 2 mm/year had a higher risk of malignancy (5-year risk = 45.5% vs 1.8%; P < .001). Conclusions: In combination with cyst size and the presence of mural nodules, cyst growth rate could be used to predict malignancy in patients with Br-IPMN. [Copyright &y& Elsevier]

Simple Summary: FOLFIRINOX is a platinum-based chemotherapy regimen for patients with pancreatic cancer and is known to be more effective in the presence of the BRCA mutation, one of the DNA damage repair (DDR) gene mutations. However, BRCA mutations are less common in pancreatic cancer patients, accounting for only about 5% of cases worldwide, and are known to be even rarer in Asians. Therefore, this study aimed to uncover new genetic variants of DDR genes related to the response of FOLFIRINOX by analyzing variants of DDR genes using whole exome sequencing. Multivariable Cox regression analysis adjusted for clinical variables showed that a single nucleotide polymorphism (SNP) of the ERCC6 gene is an independent predictor for progression-free survival. If validated, the ERCC6 SNP found in this study could be used as a biomarker to predict responses to FOLFIRINOX. FOLFIRINOX is currently one of the standard chemotherapy regimens for pancreatic cancer patients, but little is known about the factors that can predict a response to it. We performed a study to discover novel DNA damage repair (DDR) gene variants associated with the response to FOLFIRINOX chemotherapy in patients with pancreatic cancer. We queried a cohort of pancreatic cancer patients who received FOLFIRINOX chemotherapy as the first treatment and who had tissue obtained through an endoscopic ultrasound-guided biopsy that was suitable for DNA sequencing. We explored variants of 148 DDR genes based on whole exome sequencing and performed multivariate Cox regression to find genetic variants associated with progression-free survival (PFS). Overall, 103 patients were included. Among 2384 variants of 141 DDR genes, 612 non-synonymous variants of 123 genes were selected for Cox regression analysis. The multivariate Cox model showed that rs2228528 in ERCC6 was significantly associated with improved PFS (hazard ratio 0.54, p = 0.001). The median PFS was significantly longer in patients with rs2228528 genotype AA vs. genotype GA and GG (23.5 vs. 16.2 and 8.6 months; log-rank p < 0.001). This study suggests that rs2228528 in ERCC6 could be a potential predictor of response to FOLFIRINOX chemotherapy in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated the influence of cathepsin B (CATB), a downstream target of Hedgehog (Hh) signaling, in pancreatic cancer. Cyclopamine (Hh signal inhibitor) suppressed expression of Shh, as well as Hh-induced transcription factor Gli1, and induced apoptosis in Shh-positive pancreatic cancer cell line (PANC-1). Microarray analysis revealed CATB as a gene downregulated by Hh. Cyclopamine reduced CATB protein and mRNA levels. Cyclopamine or CATB inhibitor reduced PANC-1 cell invasiveness (P <0.05). CATB expression in human pancreatic cancer tissues tended to correlate with Shh expression (P =0.053). Conclusively, Hh targets CATB and Hh signaling through CATB might influence pancreatic cancer cell invasiveness. [Copyright &y& Elsevier]

Abstract: Apigenin is a dietary flavonoid possessing therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and apigenin enhanced anti-tumor efficacy in pancreatic cancer. In vitro, the combination treatment resulted in more growth inhibition and apoptosis through the down-regulation of NF-κB activity with suppression of Akt activation in pancreatic cancer cell lines (MiaPaca-2, AsPC-1). In vivo, the combination therapy augmented tumor growth inhibition through the down-regulation of NF-κB activity with the suppression of Akt in tumor tissue. The combination of gemcitabine and apigenin enhanced anti-tumor efficacy through Akt and NF-κB activity suppression and apoptosis induction. [Copyright &y& Elsevier]

Abstract: A novel hybrid synthetic histone deacetylase inhibitor, SK-7041, was synthesized from hydroaxamic acid of trichostatin A (TSA) and pyridyl ring of MS-275. TSA and SK-7041 both induced apoptosis and G2-M cell cycle arrest in pancreatic cancer cell lines. The expressions of p21 and cyclin D2 were up-regulated and that of cyclin B1 was down-regulated by TSA or SK-7041. The expression levels of Mcl-1 and Bcl-XL but not those of Bcl-2, Bax, and Bak were suppressed by TSA or SK-7041 treatment. SK-7041 or TSA induced apoptosis and G2-M cell cycle arrest by up-regulating p21 and down-regulating cyclin B1, Mcl-1, and Bcl-XL. [Copyright &y& Elsevier]